CTIM-14. RANDOMIZED PHASE II OPEN LABEL STUDY OF NIVOLUMAB PLUS STANDARD DOSE BEVACIZUMAB VS NIVOLUMAB PLUS LOW DOSE BEVACIZUMAB IN RECURRENT GLIOBLASTOMA (RGBM). NIVOLUMAB BENEFITS OLDER POPULATION

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi52-vi52
Author(s):  
Manmeet Ahluwalia ◽  
David Peereboom ◽  
Yasmeen Rauf ◽  
Patrick Wen ◽  
David Reardon
Keyword(s):  
Overall Survival ◽  
Low Dose ◽  
Standard Dose ◽  
Performance Status ◽  
Methylation Status ◽  
Progression Free Survival ◽  
Recurrent Glioblastoma ◽  
Dose Effect ◽  
Open Label ◽  
Anti Vegf

Abstract BACKGROUND Approaches using anti-PD1 therapy alone in rGBM is of limited efficacy. VEGF is upregulated proangiogenic growth factor in GBM that contributes to tumor-associated immunosuppression. Preclinical data suggests a potential dose effect of anti-VEGF therapy on immunomodulation. Hence, a combination of anti-PD1 and anti-VEGF may be a promising approach in rGBM. METHODS 90 patients with GBM at first recurrence were randomized (1:1) to nivolumab (240 mg IV Q2 weeks) with bevacizumab at standard (10 mg/kg; Arm A) or at low dose (3 mg/kg; Arm B) IV Q2 weeks. Stratification included extent of resection, age, performance status and MGMT methylation status. Progression-free survival (PFS) and overall survival (OS) were compared between two arms. RESULTS 90 patients (Median age 60.6 years ranged 27.4-86.4, 67.8% male, median KPS 80) were enrolled between May 2018 and Jan 2020. Patients were followed in median 7.7 months (Range 0.7, 28.2). 35 patients were MGMT methylated and 53 patients were MGMT not hypermethylated and 2 were indeterminate. Overall Survival was not significantly different between arm A and arm B (1 year: 41.1 vs 37.7%, p=0.14), while OS was better for arm A in age > 60 (At 1-year: 46.2% vs 23.8%; Median: 10.6 vs 5.9 months; P=0.046). OS was no different in the two arms for age ≤ 60 years (At 1-year: 35.6% vs 56.4; Median 8.0 vs 12.4 months; P=0.90). Most frequent toxicities ( >20%) included fatigue (45.6%), proteinuria (34.4 %), diarrhea (28.9%), hypertension (23.3%) and lipase increase (21.1%). Toxicities in grade 3-4 were hypertension (7.8%), fatigue (5.6) and other non-neurological toxicities including DVT, PE, infection, and abnormal liver function. CONCLUSIONS Overall PFS and OS rates appear similar for nivolumab with either standard or low-dose bevacizumab compared to historical benchmarks of bevacizumab monotherapy. Nivolumab with standard bevacizumab seem to benefit patients older than 60 years old.

Randomized phase 2 study of nivolumab (nivo) plus either standard or reduced dose bevacizumab (bev) in recurrent glioblastoma (rGBM).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 2015-2015
Author(s):  
Manmeet Singh Ahluwalia ◽  
Yasmeen Rauf ◽  
Hong Li ◽  
Patrick Y. Wen ◽  
David M. Peereboom ◽  
...  
Keyword(s):  
Single Cell ◽  
Rna Sequencing ◽  
Low Dose ◽  
Methylation Status ◽  
Post Treatment ◽  
Dose Effect ◽  
Blood Samples ◽  
Treatment Standard ◽  
Anti Vegf ◽  
Single Cell Rna Sequencing

2015 Background: Trials with anti-PD1 in rGBM have shown limited efficacy. VEGF is highly up regulated proangiogenic growth factor in GBM contributing to tumor-associated immunosuppression. Preclinical data suggests a potential dose effect of anti-VEGF therapy on immunomodulation. Hence, a combination of anti-PD1 and anti-VEGF may be a promising approach in rGBM. Methods: 90 patients with first-recurrent GBM were randomized (1:1) to nivolumab (240 mg IV Q2 weeks) with bevacizumab at standard (10 mg/kg; Arm A) or at low dose (3 mg/kg; Arm B) IV Q2 weeks. Stratification included extent of resection, age, performance status and MGMT methylation status. Single cell RNA sequencing with CITE-seq was used to analyze blood samples from pre- and 8 weeks post-treatment among 8 responders and 8 non-responders. Progression-free survival (PFS) and overall survival (OS) were compared between two arms. Results: 90 patients (Median age 60.6 years ranged 27.4-86.4, 67.8% male, median KPS 80) were enrolled between May 2018 and Jan 2020. Patients were followed in median 7.7 months (Range 0.7, 28.2). 35 of 88 patients were MGMT methylated (2 indeterminate). Overall OS was not significantly different between arm A and arm B (1 year: 41.1 vs 37.7%, p = 0.14), while OS was better for arm A in age > 60 (At 1-year: 46.2% vs 23.8%; Median: 10.6 vs 5.9 months; P = 0.046). OS was no different in the two arms for age ≤ 60 years (At 1-year: 35.6% vs 56.4; Median 8.0 vs 12.4 months; P = 0.90). Single cell RNA sequencing with CITE-seq was used to analyze blood samples from 16 patients, baseline and 8 weeks post treatment. Standard dose bevacizumab treated patients had decreased myeloid derived suppressor cells and an inflammatory response gene signature at 8 weeks. Most frequent toxicities ( > 20%) included fatigue (45.6%), proteinuria (34.4 %), diarrhea (28.9%), hypertension (23.3%) and lipase increase (21.1%). Toxicities in grade 3-4 were hypertension (7.8%), fatigue (5.6) and other non-neurological toxicities including DVT, PE, infection, and abnormal liver function. Conclusions: Overall PFS and OS rates appear similar for nivolumab with either standard or low-dose bevacizumab compared to historical benchmarks of bevacizumab monotherapy. Nivolumab with standard bevacizumab may benefit older but not younger patients. Ongoing response evaluation and immunocorrelative data will be presented. Clinical trial information: NCT03452579.

scholarly journals Axitinib plus avelumab in the treatment of recurrent glioblastoma: a stratified, open-label, single-center phase 2 clinical trial (GliAvAx)

2020 ◽  
Vol 8 (2) ◽  
pp. e001146
Author(s):  
Gil Awada ◽  
Laila Ben Salama ◽  
Jennifer De Cremer ◽  
Julia Katharina Schwarze ◽  
Lydia Fischbuch ◽  
...  
Keyword(s):  
Adverse Events ◽  
Group Performance ◽  
Performance Status ◽  
Objective Response ◽  
Eastern Cooperative Oncology Group ◽  
Progression Free Survival ◽  
Recurrent Glioblastoma ◽  
Synergistic Activity ◽  
Open Label ◽  
Corticosteroid Dose

BackgroundNo treatment demonstrated to improve survival in patients with recurrent glioblastoma (rGB) in a randomized trial. Combining axitinib with the programmed cell death ligand 1 blocking monoclonal antibody avelumab may result in synergistic activity against rGB.MethodsAdult patients with rGB following prior surgery, radiation therapy and temozolomide chemotherapy were stratified according to their baseline use of corticosteroids. Patients with a daily dose of ≤8 mg of methylprednisolone (or equivalent) initiated treatment with axitinib (5 mg oral two times per day) plus avelumab (10 mg/kg intravenous every 2 weeks) (Cohort-1). Patients with a higher baseline corticosteroid dose initiated axitinib monotherapy; avelumab was added after 6 weeks of therapy if the corticosteroid dose could be tapered to ≤8 mg of methylprednisolone (Cohort-2). Progression-free survival at 6 months (6-m-PFS%), per immunotherapy response assessment for neuro-oncology criteria, served as the primary endpoint.ResultsBetween June 2017 and August 2018, 54 patients (27 per cohort) were enrolled and initiated study treatment (median age: 55 years; 63% male; 91% Eastern Cooperative Oncology Group Performance Status 0–1). Seventeen (63%) patients treated in Cohort-2 received at least one dose of avelumab. The 6-m-PFS% was 22.2% (95% CI 6.5% to 37.9%) and 18.5% (95% CI 3.8% to 33.2%) in Cohort-1 and Cohort-2, respectively; median overall survival was 26.6 weeks (95% CI 20.8 to 32.4) in Cohort-1 and 18.0 weeks (95% CI 12.5 to 23.5) in Cohort-2. The best objective response rate was 33.3% and 22.2% in Cohort-1 and Cohort-2, respectively, with a median duration of response of 17.9 and 19.0 weeks. The most frequent treatment-related adverse events were dysphonia (67%), lymphopenia (50%), arterial hypertension and diarrhea (both 48%). There were no grade 5 adverse events.ConclusionThe combination of avelumab plus axitinib has an acceptable toxicity profile but did not meet the prespecified threshold for activity justifying further investigation of this treatment in an unselected population of patients with rGB.

scholarly journals RBTT-01. RANDOMIZED PHASE 2 OPEN LABEL STUDY OF NIVOLUMAB PLUS STANDARD DOSE BEVACIZUMAB VERSUS NIVOLUMAB PLUS LOW DOSE BEVACIZUMAB IN RECURRENT GLIOBLASTOMA

2018 ◽  
Vol 20 (suppl_6) ◽  
pp. vi234-vi234 ◽  
Author(s):  
Manmeet Ahluwalia ◽  
David Peereboom ◽  
Cathy Schilero ◽  
Deborah Forst ◽  
Eric Wong ◽  
...  
Keyword(s):  
Low Dose ◽  
Standard Dose ◽  
Recurrent Glioblastoma ◽  
Phase 2 ◽  
Open Label ◽  
Open Label Study ◽  
Label Study ◽  
Randomized Phase 2

Bevacizumab Alone and in Combination With Irinotecan in Recurrent Glioblastoma

2009 ◽  
Vol 27 (28) ◽  
pp. 4733-4740 ◽  
Author(s):  
Henry S. Friedman ◽  
Michael D. Prados ◽  
Patrick Y. Wen ◽  
Tom Mikkelsen ◽  
David Schiff ◽  
...  
Keyword(s):  
Overall Survival ◽  
Objective Response ◽  
Survival Rates ◽  
Progression Free Survival ◽  
Recurrent Glioblastoma ◽  
Survival Times ◽  
Open Label ◽  
Noncomparative Trial ◽  
End Points ◽  
Free Survival

Purpose We evaluated the efficacy of bevacizumab, alone and in combination with irinotecan, in patients with recurrent glioblastoma in a phase II, multicenter, open-label, noncomparative trial. Patients and Methods One hundred sixty-seven patients were randomly assigned to receive bevacizumab 10 mg/kg alone or in combination with irinotecan 340 mg/m2 or 125 mg/m2 (with or without concomitant enzyme-inducing antiepileptic drugs, respectively) once every 2 weeks. Primary end points were 6-month progression-free survival and objective response rate, as determined by independent radiology review. Secondary end points included safety and overall survival. Results In the bevacizumab-alone and the bevacizumab-plus-irinotecan groups, estimated 6-month progression-free survival rates were 42.6% and 50.3%, respectively; objective response rates were 28.2% and 37.8%, respectively; and median overall survival times were 9.2 months and 8.7 months, respectively. There was a trend for patients who were taking corticosteroids at baseline to take stable or decreasing doses over time. Of the patients treated with bevacizumab alone or bevacizumab plus irinotecan, 46.4% and 65.8%, respectively, experienced grade ≥ 3 adverse events, the most common of which were hypertension (8.3%) and convulsion (6.0%) in the bevacizumab-alone group and convulsion (13.9%), neutropenia (8.9%), and fatigue (8.9%) in the bevacizumab-plus-irinotecan group. Intracranial hemorrhage was noted in two patients (2.4%) in the bevacizumab-alone group (grade 1) and in three patients (3.8%) patients in the bevacizumab-plus-irinotecan group (grades 1, 2, and 4, respectively). Conclusion Bevacizumab, alone or in combination with irinotecan, was well tolerated and active in recurrent glioblastoma.

scholarly journals Regorafenib in Recurrent Glioblastoma Patients: A Large and Monocentric Real-Life Study

Cancers ◽  
2021 ◽  
Vol 13 (18) ◽  
pp. 4731
Author(s):  
Giuseppe Lombardi ◽  
Mario Caccese ◽  
Marta Padovan ◽  
Giulia Cerretti ◽  
Giovanna Pintacuda ◽  
...  
Keyword(s):  
Overall Survival ◽  
Life Experience ◽  
Kinase Inhibitor ◽  
Performance Status ◽  
Methylation Status ◽  
Eastern Cooperative Oncology Group ◽  
Real Life ◽  
Recurrent Glioblastoma ◽  
Ecog Performance Status ◽  
Life Study

Despite multimodal treatment with surgery and radiochemotherapy, the prognosis of glioblastoma remains poor, and practically all glioblastomas relapse. To date, no standard treatment exists for recurrent glioblastoma patients and traditional therapies have showed limited efficacy. Regorafenib is an oral multi-targeted tyrosine kinase inhibitor showing encouraging benefits in recurrent GBM patients enrolled in the REGOMA trial. We performed a large study to investigate clinical outcomes and the safety of regorafenib in a real-life population of recurrent glioblastoma patients. Patients receiving regorafenib outside clinical trials at the Veneto Institute of Oncology were retrospectively reviewed. The major inclusion criteria were: histologically confirmed diagnosis of glioblastoma, prior first line therapy according to “Stupp protocol”, Eastern Cooperative Oncology Group (ECOG) performance status score ≤1. According to the original schedule, patients received regorafenib 160 mg once daily for the first 3 weeks of each 4-week cycle. The primary endpoints of the study were overall survival and safety. A total of 54 consecutive patients were enrolled. The median age was 56, MGMT methylated status was found in 28 out of 53 available patients (52.8%), IDH mutation in 5 (9.3%) and 22 patients were receiving steroids at baseline. The median overall survival was 10.2 months (95% CI, 6.4–13.9), the OS-12 was 43%. Age, MGMT methylation status and steroid use at baseline were not statistically significant on a multivariate analysis for OS. Patients reporting a disease control as best response to regorafenib demonstrated a significant longer survival (24.8 months vs. 6.2 months for patients with progressive disease, p = 0.0001). Grade 3 drug-related adverse events occurred in 10 patients (18%); 1 patient (2%) reported a grade 4 adverse event (rash maculo-papular). No death was considered to be drug-related. This study reported the first large “real-life” experience of regorafenib in recurrent glioblastoma. Overall, our results are close to the ones reported in the previous phase 2 study, despite the fact that we had a longer survival. We showed the encouraging activity and tolerability of this treatment in recurrent glioblastoma patients when used as a second-line treatment.

Safety and efficacy study of retifanlimab and epacadostat in combination with radiation and bevacizumab in patients with recurrent glioblastoma.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. TPS2070-TPS2070
Author(s):  
Jian Li Campian ◽  
Christopher Abraham ◽  
Jingqin Luo ◽  
Grayson Talcott ◽  
Ruth Katumba ◽  
...  
Keyword(s):  
Checkpoint Inhibitors ◽  
Karnofsky Performance Status ◽  
Performance Status ◽  
Treatment Options ◽  
Single Agent ◽  
Progression Free Survival ◽  
Recurrent Glioblastoma ◽  
Open Label ◽  
Eligibility Criteria ◽  
Safety And Efficacy

TPS2070 Background: Recurrent glioblastoma (rGBM) after chemoradiotherapy has a dismal outcome with very limited treatment options. Addition of reirradiation to bevacizumab appears to improve progression-free survival (PFS) but does not improve overall survival (OS). Immune checkpoint inhibitors of programmed cell death-1 (PD-1) pathway appear to have limited single-agent activity for rGBM due to its immunesuppressive microenvironment. Indoleamine 2,3 dioxygenase 1 (IDO1) is an inducible and rate-limiting enzyme that catabolizes tryptophan (Trp) into kynurenine (Kyn). IDO1 is over-expressed in 50̃90% of GBM patients, and high IDO1 levels correlate with reduced OS. Epacadostat is a highly potent and selective oral inhibitor of IDO1 and may increase tumor sensitivity to anti-PD-1 blockade. Retifanlimab is a humanized anti-PD-1 monoclonal antibody directed against PD-1. The purpose of this study is to evaluate the safety and efficacy of combining retifanlimab plus or minus epacadostat with reirradiation and bevacizumab for rGBM patients. Methods: This is an open-label nonrandomized phase II study of two sequential cohorts for bevacizumab-naïve adults with rGBM: retifanlimab + bevacizumab+ radiation (cohort A), and retifanlimab + epacadostat + bevacizumab + radiation (cohort B). Each cohort will enroll 24 evaluable patients. Key eligibility criteria include candidates for reirradiation and bevacizumab, age ≥ 18 years, Karnofsky performance status ≥ 60%, and dexamethasone dose ≤ 4 mg/day. The primary endpoint is OS. Secondary endpoints include PFS, neurologic functions, and toxicity. The correlative endpoints include studies assess the anti-glioma immune response, serum Kyn/Trp ratio, and RNA expression of IDO1 and PD-L1 from available tissue. The trial is actively enrolling. At the time of abstract submission, 16 of the planned 24 patients in Cohort A have been enrolled. Clinical trial information: NCT03532295. [Table: see text]

Randomized phase II trial comparing the efficacy of standard-dose with high-dose twice-daily thoracic radiotherapy (TRT) in limited disease small-cell lung cancer (LD SCLC).

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 9007-9007 ◽  
Author(s):  
Bjorn Henning Gronberg ◽  
Kristin Toftaker Killingberg ◽  
Øystein Fløtten ◽  
Maria Moksnes Bjaanæs ◽  
Tesfaye Madebo ◽  
...  
Keyword(s):  
Overall Survival ◽  
Primary Endpoint ◽  
Median Overall Survival ◽  
Standard Dose ◽  
Performance Status ◽  
Progression Free Survival ◽  
Cranial Irradiation ◽  
Prophylactic Cranial Irradiation ◽  
High Dose ◽  
Grade 3

9007 Background: Concurrent chemoradiotherapy is the standard treatment of LD SCLC. Some patients are cured, but most relapse and better treatment is needed. 45 Gy in 30 fractions BID is the most recommended TRT-schedule. Studies suggest that a higher TRT-dose might prolong survival, but hitherto, this has not been confirmed in randomized trials. We aimed to investigate whether high-dose BID TRT of 60 Gy in 40 fractions was feasible, tolerated, and improved survival. Methods: Patients > 18 years, performance status (PS) 0-2 and confirmed LD SCLC were to receive 4 courses of platinum/etoposide and were randomized to BID TRT of 60 or 45 Gy. Responders were offered prophylactic cranial irradiation of 25-30 Gy. Primary endpoint was 2-year survival; secondary endpoints were toxicity, progression free survival (PFS), and overall survival (OS). To demonstrate a 25% improvement of 2-year survival from 53% to 66% with a one-sided α = .10 and β = .80, 75 patients were required on each arm. Results: Between 2014-2018, 176 patients were enrolled at 22 Scandinavian hospitals. 160 completed TRT per protocol and were eligible for the present analyses (60 Gy: n = 84, 45 Gy: n = 76). Median age was 65, 58% women, 90% PS 0-1. There were no significant differences in grade 3–4 esophagitis (60 Gy: 19%, 45 Gy: 18%, p = .92) or grade 3–4 pneumonitis (60 Gy: 4%, 45 Gy: 0%, p = .10). There was a trend towards more neutropenic infections on the 45 Gy arm (60 Gy: 21%, 45 Gy: 36%, p = .05). There were no significant differences in other grade 3-4 toxicity. Three patients died during the study treatment period (60 Gy: one neutropenic infection and one aortic dissection; 45 Gy: one thrombocytopenic bleeding). There were no statistically significant differences in response rates (60 Gy: 88% [95% CI 81-95], 45 Gy: 85% [95% CI 76-93], p = .52) or median PFS (60 Gy: 20 months [95% CI 11-29], 45 Gy: 14 months [95% CI 10-19], p = .31). Significantly more patients on the 60 Gy arm were alive after 2 years (60 Gy: 73% [95% CI 63-83], 45 Gy: 46% [95% CI 36-60], p = .001), and they had a significantly longer median overall survival (60 Gy: 42 months [95% CI 32-51], 45 Gy: 23 months [95% CI 17-28], HR .63 [95% CI .41-.96], p = .031). Conclusions: LD SCLC patients who received BID TRT of 60 Gy had a statistically significant and numerically substantial benefit in terms of 2-year survival (primary endpoint) and median overall survival compared with those who received BID TRT of 45 Gy. The higher TRT dose did not cause more toxicity than the standard dose. Clinical trial information: NCT02041845.

scholarly journals ACTR-26. SAFETY AND EFFICACY OF BEVACIZUMAB PLUS TTFIELDS IN PATIENTS WITH RECURRENT GLIOBLASTOMA (GBM): DATA FROM A PHASE II CLINICAL TRIAL

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi18-vi18 ◽  
Author(s):  
Jaleh Fallah ◽  
Rekha Chaudhary ◽  
Lisa Rogers ◽  
Wei (Auston) Wei ◽  
Cathy Brewer ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Overall Survival ◽  
Disease Progression ◽  
Muscle Weakness ◽  
Progression Free Survival ◽  
Recurrent Glioblastoma ◽  
Open Label ◽  
Safety And Efficacy ◽  
Phase 2 Clinical Trial ◽  
Recurrent Gbm

Abstract BACKGROUND Studies of bevacizumab monotherapy and TTFields monotherapy have shown activity but limited clinical benefit in patients with recurrent GBM. In an open label, single-arm, phase 2 clinical trial, the safety and efficacy of the combination of bevacizumab and TTFields was studied in patients with recurrent GBM. METHOD Bevacizumab-naïve patients with histologically confirmed GBM or other grade IV glioma, with recurrent disease after radiotherapy and temozolomide chemotherapy, were eligible. Bevacizumab dose was 10mg/kg intravenously every 2 weeks and TTFields was worn at least 18 hours daily. The primary endpoint was safety, progression-free survival at 6 months (PFS6) and overall survival at 12 months (OS12). Treatment was continued until disease progression or unacceptable toxicity. Survival outcomes were assessed using the Kaplan-Meier method. Treatment-related adverse events were reported according to CTCAE, v4.0 criteria. RESULTS 25 patients were enrolled and 23 were eligible for data analysis: 18 (78%) men and 5 (22%) women, median age 60 years (range 17–78). 21 patients were Caucasian, 1 was African American and 1 of unknown race. Median follow-up was 6.0 months (range 2.4–22). Seven patients (30 %) had disease progression. Median PFS was 9.9 (95% CI: 6.7-NA) months. PFS rate at 6 months (PFS6) was 71% (95% CI: 0.54–0.94). Median overall survival was 9.9 (95%CI 7.3-NA) months. OS rate at 12 months (OS12) was 42% (95%CI 0.24–0.74). 7 patients (30%) had grade 3 toxicity (cough, dysphagia, muscle weakness, hyperglycemia, hypertension, psychosis, seizure, lymphopenia, transaminitis). 1 patient developed grade 4 muscle weakness in the lower extremities. CONCLUSION Treatment with the combination of bevacizumab and TTFields in patients with recurrent GBM is safe and feasible and has shown clinical efficacy.

scholarly journals CTIM-12. RANDOMIZED PHASE 2 STUDY OF NIVOLUMAB (NIVO) PLUS EITHER STANDARD OR REDUCED DOSE BEVACIZUMAB (BEV) IN RECURRENT GLIOBLASTOMA (rGBM)

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii35-ii35
Author(s):  
Manmeet Ahluwalia ◽  
David Peereboom ◽  
Yasmeen Rauf ◽  
Justin Lathia ◽  
Tyler Alban ◽  
...  
Keyword(s):  
Single Cell ◽  
Rna Sequencing ◽  
Low Dose ◽  
Methylation Status ◽  
Post Treatment ◽  
Dose Effect ◽  
Blood Samples ◽  
Treatment Standard ◽  
Anti Vegf ◽  
Single Cell Rna Sequencing

Abstract BACKGROUND Trials with anti-PD1 in rGBM have shown limited efficacy. VEGF is highly upregulated proangiogenic growth factor in GBM contributing to tumor-associated immunosuppression. Preclinical data suggests a potential dose effect of anti-VEGF therapy on immunomodulation. Hence, a combination of anti-PD1 and anti-VEGF may be a promising approach in rGBM. METHODS 90 patients with first-recurrent GBM were randomized (1:1) to nivolumab (240 mg IV Q2 weeks) and bevacizumab at standard (10 mg/kg; Arm A) or low dose (3 mg/kg; Arm B) IV Q2 weeks. Eligibility also required KPS≥ 70% and dexamethasone ≤ 4 mg/day. Stratification included extent of resection, age, performance status and MGMT methylation status. Single cell RNA sequencing with CITE-seq was used to analyze blood samples from pre- and 8 weeks post-treatment among 8 responders and 8 non-responders. RESULTS 90 patients were enrolled (May 2018- Jan 2020) and median follow-up is 7.5 months. Characteristics in 2 arms were comparable. Median age was 60.5 years (range 27–86), median KPS was 80. 35 patients were MGMT methylated, 53 unmethylated and 2 indeterminate. Estimated progression free survival (PFS) and median overall survival (OS) in arm A are 6.13 and 10.85 months and 4.59 and 9.61 months in Arm B, respectively. Single cell RNA sequencing with CITE-seq was used to analyze blood samples from 16 patients, baseline and 8 weeks post treatment. Standard dose bevacizumab treated patients had decreased myeloid derived suppressor cells and an inflammatory response gene signature at 8 weeks. Most frequent toxicities included fatigue (52.8%), headache (32.6%), diarrhea (31.5%), proteinuria (25.8) and hypertension (23.6%). Toxicity was comparable between 2 arms, except hypertension was more common in arm A. CONCLUSIONS PFS and OS rates appear similar for nivolumab with either standard or low-dose bevacizumab compared to historical benchmarks of bevacizumab monotherapy. Ongoing response evaluation and immunocorrelative data will be presented.

Phase IIa trial of cilengitide (EMD121974) single-agent therapy in patients (pts) with recurrent glioblastoma (GBM): EMD 121974-009

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 2002-2002 ◽  
Author(s):  
D. Reardon ◽  
K. Fink ◽  
B. Nabors ◽  
T. Cloughesy ◽  
S. Plotkin ◽  
...  
Keyword(s):  
Karnofsky Performance Status ◽  
Performance Status ◽  
Single Agent ◽  
Progression Free Survival ◽  
Median Number ◽  
Recurrent Glioblastoma ◽  
Tumor Control ◽  
Clinical Activity ◽  
Open Label ◽  
Recurrent Gbm

2002 Background: Our phase IIa study evaluated the safety, toxicity, and clinical activity of the cyclic RGD pentapeptide cilengitide (EMD121974), an inhibitor of integrins avβ3 and avβ5, as a single agent at doses of 500 and 2000 mg in pts with recurrent GBM. Methods: In this multicenter, open-label, randomized, uncontrolled study, pts with GBM and measurable disease that had relapsed after previous temozolomide and radiotherapy were randomized to receive cilengitide at either 500 mg or 2000 mg i.v., 2x/week, until progression. Neurologic exams were performed after every cycle (4 weeks) and MRIs were performed every other cycle. Central, blinded pathology and radiology reviews were performed. The primary endpoint was Progression Free Survival (PFS) at 6 months (6-mth PFS). Secondary endpoints included response, survival, time to disease progression, safety, tolerability and pharmacokinetics (PK). Results: 81 pts accrued (median Karnofsky Performance Status 80%; median age 57 yrs) at 15 sites including 41 at the 500 mg and 40 at the 2000 mg dose levels. Demographic and pretreatment variables were comparable between dose level cohorts. The median number of infusions was 16 [range, 4–179]. PK studies revealed significantly greater exposures among the 2000 mg cohort. Treatment related NCI CTC grade 3 adverse events (AEs) included elevated transaminases (at 500 mg), arthralgia/ myalgia (at 500 mg), and weight increase/ edema (at 2000 mg) in 1 patient, respectively. No grade 4 therapy related AEs were reported. One CTC grade 2 cerebral hemorrhage was reported in a pt at progression. The 6- mth PFS was 16.1% (n=13/81 pts). 10 pts (12.3 %, n=4 with 500 mg, n=6 with 2000 mg) received 12 or more cycles. Six pts (7.4%) remain progression-free and on treatment. Median Overall Survival (mOS) was 6.5 mths [95% CI: 5.2–9.3 mths] in the 500 mg arm and 9.9 mths [95% CI, 6.3–15.7 mths] in the 2000 mg arm. Although not statistically significant, there was a trend towards better tumor control in pts receiving 2000 mg 2x/week. Conclusions: Cilengitide was well tolerated and demonstrated single agent activity in recurrent GBM, with long term disease stabilization in a subset of pts. [Table: see text]

Sign in / Sign up

Export Citation Format

Share Document